Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA214595 | ENA |
REPOSITORIES: ENA
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Project description:Pancreatic beta-cell dysfunction and death are central in the pathogenesis of type 2 diabetes. Saturated fatty acids cause beta-cell failure and contribute to diabetes development in genetically predisposed individuals. Here we used RNA-sequencing to map transcripts expressed in five palmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acid metabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators of adaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function, autophagy and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity. Palmitate inhibited transcription factors controlling beta-cell phenotype including PAX4 and GATA6. 59 type 2 diabetes candidate genes were expressed in human islets, and 11 were modified by palmitate. Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts. Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functions related to cell death. DAVID analysis of transcription binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA and the ER stress response regulators XBP1 and ATF6. This human islet transcriptome study identified novel mechanisms of palmitate-induced beta-cell dysfunction and death. The data point to crosstalk between metabolic stress and candidate genes at the beta-cell level. 5 human islet of Langerhans preparations examined under 2 conditions (control and palmitate treatment)
2014-01-09 | E-GEOD-53949 | biostudies-arrayexpress
Project description:Pancreatic beta-cell dysfunction and death are central in the pathogenesis of type 2 diabetes. Saturated fatty acids cause beta-cell failure and contribute to diabetes development in genetically predisposed individuals. Here we used RNA-sequencing to map transcripts expressed in five palmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acid metabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators of adaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function, autophagy and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity. Palmitate inhibited transcription factors controlling beta-cell phenotype including PAX4 and GATA6. 59 type 2 diabetes candidate genes were expressed in human islets, and 11 were modified by palmitate. Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts. Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functions related to cell death. DAVID analysis of transcription binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA and the ER stress response regulators XBP1 and ATF6. This human islet transcriptome study identified novel mechanisms of palmitate-induced beta-cell dysfunction and death. The data point to crosstalk between metabolic stress and candidate genes at the beta-cell level.
2014-01-09 | GSE53949 | GEO
Project description:Metabolic reprogramming of glucose and amino acids has been documented to affect early development. Here, we show that peroxisome-mediated β-oxidation is involved in lipids reprogramming to achieve H3K4me3 erasure and then zygotic genome activation (ZGA) in early embryo development. The metabolic patterns of fatty acids (FAs), triglyceride (TG) and phospholipid (PL) are reprogrammed during the oocyte-to-embryo transition. Very long-chain fatty acids (VLCFAs), arachidonic acid (ARA), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (Lyso-PE), lysophosphatidylcholine (Lyso-PC), and methyl donors are stored in oocytes, and after fertilization, they are converted into phosphatidylcholine (PC) at the 2-cell stage. Mitochondrial β-oxidation prevails in oocytes, while peroxisomal β-oxidation plays a critical role in shortening the VLCFA to form TG and synthesize PC and balancing the ratio of saturated and unsaturated FAs, which consumes the methyl donors as conducive to H3K4me3 erasure at the 2-cell stage. Inhibiting the peroxisome-mediated β-oxidation disrupts lipids metabolism remodellingH3K4me3 erasure and subsequent ZGA, leading to embryo arrest at the 2-cell stage. Oocytes from obese mice show I a relatively low level of VLCFAs, defective peroxisomal β-oxidation, and incomplete H3K4me3 erasure and ZGA. Microinjection of two saturated fatty acids, palmitic and myristic acids, rescues 2-cell arrest caused by peroxisome-mediated β-oxidation inhibition and obesity, and overexpressing Pemt to consume the methyl donors has the same rescue effect. These results elucidate a novel link among the peroxisomal-β-oxidation-mediated lipid metabolism reprogramming, H3K4me3 modification and ZGA during oocyte-embryo transition, and may provide a unique approach to improve reproduction in obese women.
2023-09-25 | GSE243450 | GEO
Project description:Metabolic reprogramming of glucose and amino acids has been documented to affect early development. Here, we show that peroxisome-mediated β-oxidation is involved in lipids reprogramming to achieve H3K4me3 erasure and then zygotic genome activation (ZGA) in early embryo development. The metabolic patterns of fatty acids (FAs), triglyceride (TG) and phospholipid (PL) are reprogrammed during the oocyte-to-embryo transition. Very long-chain fatty acids (VLCFAs), arachidonic acid (ARA), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (Lyso-PE), lysophosphatidylcholine (Lyso-PC), and methyl donors are stored in oocytes, and after fertilization, they are converted into phosphatidylcholine (PC) at the 2-cell stage. Mitochondrial β-oxidation prevails in oocytes, while peroxisomal β-oxidation plays a critical role in shortening the VLCFA to form TG and synthesize PC and balancing the ratio of saturated and unsaturated FAs, which consumes the methyl donors as conducive to H3K4me3 erasure at the 2-cell stage. Inhibiting the peroxisome-mediated β-oxidation disrupts lipids metabolism remodellingH3K4me3 erasure and subsequent ZGA, leading to embryo arrest at the 2-cell stage. Oocytes from obese mice show I a relatively low level of VLCFAs, defective peroxisomal β-oxidation, and incomplete H3K4me3 erasure and ZGA. Microinjection of two saturated fatty acids, palmitic and myristic acids, rescues 2-cell arrest caused by peroxisome-mediated β-oxidation inhibition and obesity, and overexpressing Pemt to consume the methyl donors has the same rescue effect. These results elucidate a novel link among the peroxisomal-β-oxidation-mediated lipid metabolism reprogramming, H3K4me3 modification and ZGA during oocyte-embryo transition, and may provide a unique approach to improve reproduction in obese women.
2023-09-07 | GSE242263 | GEO
Project description:Solid evidence indicates that intake of marine n-3 fatty acids lower serum triglycerides, and that replacing saturated fatty acids (SFA) with polyunsaturated fatty acids (PUFA) reduces plasma total cholesterol and LDL-cholesterol. The molecular mechanisms underlying these health beneficial effects are however not completely elucidated. The aim of this study was to investigate the expression of genes related to lipid metabolism in peripheral blood mononuclear cells (PBMC) depending on the plasma levels of n-6 and n-3 fatty acids and the SFA to PUFA ratio.
2019-03-08 | GSE111567 | GEO
Project description:Stearoyl-CoA desaturase (SCD) is the rate-limiting enzyme catalyzing the conversion of saturated fatty acids palmitate and stearate to monounsaturated fatty acids palmitoleate and oleate. During adipocyte differentiation, SCD expression increases concomitantly with several transcription factors and lipogenic genes. We used microarrays to examine gene expression in differentiated pre-adipocytes treated with and without an SCD inhibitor.
2014-04-04 | GSE51905 | GEO
Project description:Scope: Consumption of industrial trans fatty acids unfavourably alters plasma cholesterol and has been linked to NAFLD. However, the mechanisms underlying these deleterious effects of trans fatty acids are unclear. Here, we aim to investigate the molecular mechanisms of action of industrial trans fatty acids. Methods & Results: Hepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells showed that elaidate but not oleate or palmitate induced expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate was mediated by increased SREBP2 and dependent on SCAP, yet independent of LXR and UBXD8. Elaidate decreased intracellular free cholesterol levels and repressed the anti-cholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increased the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, ALT activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets. Conclusion: Elaidate induces cholesterogenesis in vitro via activation of the SCAP-SREBP axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.
2019-08-27 | GSE136278 | GEO
Project description:Scope: Consumption of industrial trans fatty acids unfavourably alters plasma cholesterol and has been linked to NAFLD. However, the mechanisms underlying these deleterious effects of trans fatty acids are unclear. Here, we aim to investigate the molecular mechanisms of action of industrial trans fatty acids. Methods & Results: Hepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells showed that elaidate but not oleate or palmitate induced expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate was mediated by increased SREBP2 and dependent on SCAP, yet independent of LXR and UBXD8. Elaidate decreased intracellular free cholesterol levels and repressed the anti-cholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increased the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, ALT activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets. Conclusion: Elaidate induces cholesterogenesis in vitro via activation of the SCAP-SREBP axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.
2019-08-27 | GSE136271 | GEO
Project description:Scope: Consumption of industrial trans fatty acids unfavourably alters plasma cholesterol and has been linked to NAFLD. However, the mechanisms underlying these deleterious effects of trans fatty acids are unclear. Here, we aim to investigate the molecular mechanisms of action of industrial trans fatty acids. Methods & Results: Hepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells showed that elaidate but not oleate or palmitate induced expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate was mediated by increased SREBP2 and dependent on SCAP, yet independent of LXR and UBXD8. Elaidate decreased intracellular free cholesterol levels and repressed the anti-cholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increased the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, ALT activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets. Conclusion: Elaidate induces cholesterogenesis in vitro via activation of the SCAP-SREBP axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.
2019-08-27 | GSE136351 | GEO
Project description:ANGPTL4 regulates plasma triglyceride levels by inhibiting lipoprotein lipase. Inactivation of ANGPTL4 decreases plasma triglycerides and reduces risk of coronary artery disease. Unfortunately, targeting ANGPTL4 for the therapeutic management of dyslipidemia and atherosclerosis is hampered by the observation that mice and monkeys in which ANGPTL4 is inactivated exhibit lipid accumulation in mesenteric lymph nodes. In mice these pathological events exclusively unfold upon feeding a high saturated fatty acid diet and are followed by an ultimately lethal pro-inflammatory response and chylous ascites. Here we show that Angptl4-/- mice fed a diet rich in trans fatty acids develop numerous lipid-filled giant cells in their mesenteric lymph nodes, yet do not have elevated serum amyloid and haptoglobin, do not exhibit ascites, and survive, unlike Angptl4-/- mice fed a saturated fatty acid-rich diet. In RAW264.7 macrophages the saturated fatty acid palmitate markedly increases markers of inflammation and the unfolded protein response, whereas the trans-unsaturated elaidate and the cis-unsaturated oleate have the opposite effect. In conclusion, trans and saturated fatty acids have very distinct biological effects. Furthermore, lipid accumulation in mesenteric lymph nodes is uncoupled from activation of an acute-phase response and chylous ascites, suggesting that ANGPTL4 should not be fully dismissed as target for dyslipidemia.
2017-04-27 | GSE98303 | GEO